Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: The randomized DYNAMIC trial.
Authors: Jeanne Tie, Joshua Cohen, Kamel Lahouel, Serigne N. Lo, Yuxuan Wang, Rachel Wong, Jeremy David Shapiro, Samuel J. Harris, Muhammad Adnan Khattak, Matthew E. Burge, Marion Harris, James F. Lynam, Louise M. Nott, Fiona Day, Theresa Hayes, Nickolas Papadopoulos, Cristian Tomasetti, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2022)

LBA100 Background: The role of adjuvant chemotherapy (CT) in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival (RFS), while its absence predicts a low recurrence risk. For ctDNA-positive cases the benefit of adjuvant CT is unknown. DYNAMIC was designed to assess if a ctDNA-guided approach could reduce the use of adjuvant CT without compromising recurrence risk. Methods: DYNAMIC is a multi-center randomized controlled phase II trial. Eligible patients had resected stage II colon cancer and were suitable for adjuvant CT. Patients were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria), after stratification for T stage and participating center location. Criteria for clinical low versus high risk were predefined. The Safe-SeqS tumor-informed personalized ctDNA assay was used. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine CT; ctDNA-negative patients were not treated. The primary efficacy endpoint was non-inferiority in RFS rate at 2 years. A key secondary endpoint was adjuvant CT use. The target sample size of 450 provided 80% power with 95% confidence to confirm non-inferiority between the two arms with a margin of 8.5%. Results: Of 455 patients randomized between Aug 2015 and Aug 2019, 302 were assigned to ctDNA-guided and 153 to standard management. Median follow-up was 37 months. In the ctDNA-guided arm, ctDNA analysis was successful in all but three patients; only two patients did not receive ctDNA-guided management. In the intention to treat population, fewer patients overall in the ctDNA-guided arm received adjuvant CT compared to standard management (15.3% vs 27.9%, odds ratio 2.14; P = 0.002), with the largest difference seen in patients with T4 or poorly differentiated tumors (odds ratios 6.22 and 6.31, respectively). Of those who received treatment, oxaliplatin-based doublet was more frequently administered than fluoropyrimidine alone for ctDNA-guided compared to standard management patients (62.2% vs. 9.8%; P &lt; 0.001). ctDNA-guided management was non-inferior to standard management for 2-year RFS (93.5% vs 92.4%, difference 1.1%, 95% confidence interval, -4.1% to 6.2%). Following adjuvant CT, 3-year RFS for ctDNA-positive patients was 86.4%. Without adjuvant CT, 3-year RFS for ctDNA-negative patients was 92.5%, with a 3-year RFS of 96.7% in the clinical low risk subgroup. Conclusions: A ctDNA-guided approach to stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. The low recurrence rate in ctDNA-positive patients who received chemotherapy suggests a survival benefit from adjuvant therapy. ctDNA-negative patients are unlikely to benefit from chemotherapy. Clinical trial information: ACTRN12615000381583.